Neuromodulation device

ABSTRACT

This disclosure provides an apparatus or system for the modulation of neural activity in the cervical sympathetic chain (CSC) or superior cervical ganglion (SCG) or SCG post-ganglionic branch(es) and for the treatment of sleep apnoea, as well as methods for their use.

BACKGROUND

Sleep apnoea is a condition in which normal breathing is interspersed byepisodes of complete ventilatory silence and/or erratic (non-eupnoeic)breathing. These episodes of sleep apnoea and erratic breathingtypically occur during the rapid-eye movement (REM) phase of the sleepcycle. Symptoms of sleep apnoea include fatigue, cognitive impairment(for example slower reaction time, impaired memory), hypertension, andvision problems.

Sleep apnoea may be classified as central sleep apnoea or obstructivesleep apnoea, with many subjects having both. Central sleep apnoea (CSA)is due to inadequate neural control of respiratory muscles and lack ofrespiratory drive. Obstructive Sleep Apnoea (OSA) is a disordercharacterised by repetitive collapse and reopening of the upper airwayduring sleep, which impairs ventilation and can result in intermittenthypoxemia and hypercapnia. OSA is a multifactorial disorder and thepathophysiological factors that contribute to OSA include reduced upperairway dilator muscle activity during sleep, upper airway anatomicalfeatures that vary from normal, insufficient ventilatory control anddiminished lung volume. OSA has been shown to be a major risk factor fordeveloping diabetes, hypertension, atrial fibrillation, heart failureand sudden death.

Ventilation is a neurally and mechanically active (inspiration) andpassive (expiration) process. The involuntary control of breathing isdriven by the respiratory neural network in the brainstem and is in partmediated via increased activity of diaphragmatic and chest-wall muscles(via increased drive from the phrenic and intercostal nerves).

Attempts to treat CSA have included diaphragmatic pacing. Such pacinguses a device which stimulates the phrenic nerve (motor nerve drivingthe diaphragm) via an intravascular lead. Attempts to treat OSA haveincluded hypoglossal nerve stimulation, using a closed-loop reactiveunit that triggers stimulation of the hypoglossal nerve upon detectionof absence of chest movement (using an impedance sensor).

SUMMARY OF INVENTION

The present disclosure describes an apparatus or system for treatingsleep apnoea in a subject. The apparatus or system includes at least oneneural interfacing element configured to deliver a signal to at leastone cervical sympathetic chain (“CSC”), superior cervical ganglion (SCG)and/or a postganglionic branch thereof of the subject; and a controlleroperably coupled to the neural interfacing element. The controllerprograms the neural interfacing element to deliver a signal thatincreases localized sympathetic activity of the CSC, SCG and/or apostganglionic branch thereof, thereby increasing sympathetic activityof the CSC, SCG and/or a postganglionic branch thereof and amelioratingsleep apnoea in the subject.

Also described is an apparatus or system for modulating the neuralactivity of a CSC, SCG and/or a postganglionic branch thereof of asubject. The apparatus or system includes a neural interfacing elementhaving one or more transducers each configured to apply a signal to aCSC, SCG and/or a postganglionic branch thereof of the subject; and acontroller operably coupled to the one or more transducers. Thecontroller controlling the signal to be applied by the transducer(s),such that the signal stimulates increased localized sympathetic neuralactivity in the CSC, SCG and/or a postganglionic branch thereof. Saidincrease in localized sympathetic activity is then able to produce aphysiological response in the subject.

Optionally, the neural interfacing element is configured to deliver asignal to the superior cervical ganglia (“SCG”) and/or one or morepost-ganglionic branch(es) thereof. Optionally, two or more neuralinterfacing elements (e.g., two or more transducers) are positionedbilaterally to increase localized sympathetic activity of the right andleft CSC, SCG and/or a postganglionic branch thereof.

Favourably, the neural interfacing element is implantable. Such animplantable neural interfacing element is preferably less than 1 cc insize.

Also described are methods for increasing sympathetic activity in a CSC,SCG and/or a postganglionic branch thereof of a subject. The methodinvolves: i) implanting in the subject at least a portion of anapparatus or system as disclosed herein; ii) positioning at least oneneural interfacing element (e.g., a transducer) of the apparatus orsystem in signalling contact with a CSC, SCG and/or a postganglionicbranch thereof of the subject; and iii) activating the apparatus orsystem.

Favourably, the method ameliorates sleep apnoea in a subject, and thusis a method of treating sleep apnoea in a patient. As indicated above,such methods involve delivering a signal to a CSC, SCG and/or apostganglionic branch thereof of the subject to stimulate neuralactivity in the nerve.

Also described herein is a method of treating sleep apnoea in a subject,the method comprising delivering a signal to a CSC, SCG and/or apostganglionic branch thereof of the subject to stimulate neuralactivity in said CSC, SCG and/or a postganglionic branch thereof in thesubject. Optionally the signal is delivered by a neural interfacingelement (e.g. a transducer) of an apparatus or system as describedherein. Optionally the signal is delivered to a SCG and/orpost-ganglionic branch(es) of the SCG in the subject. Optionally thesignal is delivered unilaterally (to the left or right CSC, SCG and/or apostganglionic branch thereof), or bilaterally.

Also disclosed are neuromodulatory electrical waveforms for use intreating sleep apnoea in a subject. Such waveforms are an alternatingcurrent (AC) or direct current (DC) waveform having a frequency of 1-50Hz, such that, when applied to a CSC, SCG and/or a postganglionic branchthereof, the waveform stimulates neural signalling in the nerve.

Also disclosed is the use of a neuromodulation device for treating sleepapnoea in a subject by stimulating neural activity in a CSC, SCG and/ora postganglionic branch thereof of the subject.

In a preferred embodiment of all aspects of the invention, the subjectis a human, e.g., a patient experiencing or suffering from sleep apnoea.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Relationship between the superior cervical ganglion and thecarotid sinus nerve: (Adapted from McDonald D M. Morphology of the ratcarotid sinus nerve. I. Course, connections, dimensions andultrastructure. J Neurocytol. 12: 345-372, 1983). Cervical sympatheticchain provides post-ganglionic sympathetic fibres to carotid sinus nerve

FIG. 2: A, B. Drawings of the ventrolateral aspect of the bifurcation ofa left common carotid artery. The panels show major nerves (N) andganglia in the region of the carotid sinus nerve. Panels A and B showthe glossopharyngeal nerve, carotid sinus nerve and carotid body. PanelA shows the jugular and nodose ganglia and branches of the vagus(black). Panel B shows the superior cervical ganglion and major branches(stippled). The names of arteries (A) present in both drawings are givenin panel B. Reconstruction from serial sections. Approximatemagnification ×17.

C-E. Drawings of the carotid body (broken line) shown in panels A and Billustrating additional features of the relationship of the sinus nerve,sympathetic nerves and a branch from the vagus nerve. Also shown arelocations of ganglion cells associated with each nerve. Panel C showsnerves near the ventrolateral third of the carotid body, Panel D showsthe middle third, and panel E shows the dorsomedial third. The arrow inpanel C marks an anastomosis between the sinus nerve and a sympatheticnerve. Panel D illustrates the sympathetic nerves that surround thecarotid body artery. Panel E shows the ganglioglomerular nerve asbranches of the external carotid nerve that project to the carotid body.Approximate magnification ×80. (Taken from McDonald D M. Morphology ofthe rat carotid sinus nerve. I. Course, connections, dimensions andultrastructure. J Neurocytol. 12: 345-372, 1983).

FIG. 3: Schematic drawings showing how apparatuses, devices and methodsaccording to the invention can be put into effect.

FIG. 4: Changes in frequency of breathing and the amount of disorderedbreaths (DR breaths) expressed as a % of total breaths before, duringand after a hypoxic-hypercapnic gas challenge in freely-movingSprague-Dawley rats (A). The frequency, duration and aggregate time ofapnoeic episodes (B). The timing of the 5 min sham electrical simulation(SHAM) or actual 2.5 Hz stimulation (10V, 2 ms) of both cervicalsympathetic chains are shown (STIM). The data are shown as mean±SEM.There were 15 rats in each group. *P<0.05, significant change from Pre.†P<0.05, STIM versus SHAM.

FIG. 5: Changes in mean arterial blood pressure (MAP, top left panel),diaphragmatic muscle EMG (top right), genioglossus muscle EMG (bottomleft) and upper airway resistance (UAR, bottom right), elicited by 5,7.5 and 10 Hz concurrent electrical stimulation (10V, 2 ms) of bothcervical sympathetic chains in sevoflurane-anesthetized SpontaneouslyHypertensive rats. The data are presented as mean±SEM. There were 12rats in each group.

FIG. 6: (A) Effects of bilateral stimulation (5 Hz, 0.8 mA, 2 ms) of thecervical sympathetic chain (CSC) on the change in upper airway pressure(UAP) of anesthetized Zucker-fat rats (12 weeks of age, 450-500 g)during a 60 second hypoxic gas (10% O₂, 90% N₂) challenge. The data arepresented as mean±SEM. There were 6 rats in each group.

(B) Effects of bilateral stimulation (7.5 Hz, 0.8 mA, 2 ms) of thecervical sympathetic chain (CSC) on the change in mean arterial bloodpressure (MAP) of anesthetized Zucker-fat rats (16 weeks of age, 800+grams) during a 60 second hypoxic gas (10% O₂, 90% N₂) challenge. Thedata are mean±SEM. There were 6 rats in each group.

FIG. 7: Genioglossus muscle EMG (GG-EMG) activity in anesthetizedZucker-fat rats (n=6, 16 weeks of age, 800+ grams) before and 3 hoursafter bilateral electrical stimulation (7.5 Hz, 0.8 mA) of the cervicalsympathetic chains. The data are presented as mean±SEM. *P<0.05,post-stimulation versus pre-stimulation or no stimulation.

FIG. 8: Changes in genioglossus muscle EMG (GG-EMG) activity inanesthetized Zucker-fat rats (16 weeks of age, 800+ g) during exposureto a hypoxic-hypercapnic gas challenge (10% O2, 5% CO2, 85% N2) withoutand with unilateral or bilateral electrical stimulation of the cervicalsympathetic chain (CSC).

FIG. 9: (A) Changes in diaphragmatic EMG activity (top trace) andarterial blood pressure (bottom trace) in in an anesthetized Zucker-fatrat elicited by electrical stimulation (0.8 mA, 7.5 Hz for 30 seconds)of the left, right or both cervical sympathetic chains (CSCs). (B)Summary of changes in mean arterial blood pressure (MAP) and respiratoryrate (RR) elicited by left, right or bilateral stimulation of the CSCsin Zucker-fat rats (16 weeks of age, 800+g, from Charles Rivers). Thedata are mean±SEM of 5 rats. *P<0.05, significant response.

FIG. 10: Changes in genioglossus-EMG, diaphragmatic-EMG and bloodpressure elicited by a hypoxic-hypercapnic gas challenge (10% O2, 8%CO2, 82% N2) in an anesthetized Zucker-fat rat (16 weeks of age, 800+g,from Charles Rivers) with and without electrical stimulation of theleft, right or both cervical sympathetic chains.

FIG. 11: Changes in mean arterial blood pressure and respiratory rate inanesthetized Zucker-fat rats (n=5, 16 weeks of age, 800+g, from CharlesRivers) elicited by electrical stimulation (0.5, 0.8, & 1.0 mA, 7.5 Hzfor 30 sec) of the left, right or both cervical sympathetic chains. Thedata are mean±SEM. *P<0.05, significant response.

FIG. 12: Lack of effect of bilateral stimulation of the hypoglossalnerve on the increases in diaphragmatic-EMG and falls in arterial bloodpressure that occur during hypoxic-hypercapnic (H-H) gas challenge (10%O₂, 5% CO₂, 85% N₂) in a Zucker-fat rat.

FIG. 13: Bilateral stimulation of CSC (bipolar electrodes) reduces upperairway pressure and affects cardio-respiratory output in anesthetizedZucker fat rats (n=5).

FIG. 14: Bilateral stimulation of CSC. Changes in stimulation frequencydifferentially impacted blood pressure and upper airway pressure (n=5).Percentage change calculated versus each rat prior to stimulation.

FIG. 15: Bilateral stimulation of CSC. Changes in stimulation pulsewidth differentially impacted Blood Pressure (BP) and upper airwaypressure (n=5). Percentage change calculated versus each rat prior tostimulation.

FIG. 16: Double plethysmography chambers were used to assess changes inairway resistance in animals after bilateral CSC stimulation (0.5 mA, 5Hz, 0.2 ms, 5 min recovery between stimuli) (conscious Zucker Fat (14wks) male rats, n=2). Response (% Change) was calculated by comparing tobaseline values, each animal was a control for itself. S1, S2 and S3 areeach separate stimulation events.

FIG. 17: Airway resistance trace during continuous bilateral CSCstimulation (0.5 mA, 5 Hz, 0.2 ms) for 3 minutes every 10 minutes.Percentage change calculated versus each rat's own baseline value.

FIG. 18: Airway resistance trace during intermittent bilateral CSCstimulation (0.5 mA, 5 Hz, 0.2 ms) of 30 s on, 30 s off for 15 minutesevery hour. Protocol was applied for 6 hours. Percentage changecalculated versus each rat's own baseline value.

FIG. 19: Whole body plethysmography chamber was used to assess changesin number of disordered breathing after bilateral intermittent CSCstimulation (0.5 mA, 5 Hz, 0.2 ms) for 1 day and after 7 days. Consciousfreely moving Zucker Fat (14 wks) male rats, n=3.

FIG. 20: Disordered breathing levels before bilateral intermittent CSCstimulation (0.5 mA, 5 Hz, 0.2 ms), after 1 day and after 7 days ofintermittent stimulation. Number of disordered breaths defined bybreaths that were two times as long as the average expiration time (Te)over inspiration time (Ti) (Te/Ti). Conscious freely moving Zucker Fat(14 wks) male (n=3).

DETAILED DESCRIPTION

The effectiveness of inspiration and expiration is critically-dependenton, among a variety of factors, the patency and open-status (position ofthe tongue) of the upper airway. Therefore, the tongue (genioglossus)and oropharyngeal muscles as well as motor drive to these muscles have acritical role in determining upper airway patency. The involuntarycontrol of breathing can be modulated by (1) descending input fromhigher brain centres (e.g., prefrontal cortex, hypothalamus) into thebrainstem to allow for adjustments in breathing that are required tomatch the physiological requirements of the body, and (2) peripheralchemoreceptors emanating from the carotid bodies (which continuallysample arterial blood pCO₂, pH and pCO₂ levels) to alert the brainstemrespiratory control centres as to any changes in arterial blood-gaschemistry. The carotid bodies detect hypoxic episodes such as thoseoccurring during sleep apnoea to trigger afferent signals that adjustcentral respiratory drive.

The superior cervical ganglia (SCG) are bilateral structures that residein close proximity to the carotid body at the trifurcation of the commoncarotid artery into the internal and external carotid arteries and theoccipital artery (FIG. 1). The SCG contains the cell bodies ofpost-ganglionic sympathetic neurons that project to a variety ofstructures in the brain (e.g., hypothalamus) in addition to the upperairways (e.g., larynx), tongue, and salivary glands (e.g., submandibulargland) as well as the phrenic nerves innervating the diaphragm, and thecarotid sinus nerves that innervate primary glomus cells (which senseblood pO₂, pCO₂ and pH levels) in the carotid bodies (shown in greaterdetail in FIG. 2). Pre-ganglionic projections in the spine (C1-C4)project to post-ganglionic neurons in each SCG via an ipsilateralcervical sympathetic chain (CSC). The CSC thus comprises pre-ganglionicneurons projecting into the SCG. The SCG also includes the cell bodiesof the post-ganglionic neurons, the axons of which project from the SCG.Stimulation of a CSC thereby increases neural activity of theipsilateral SCG, in particular in the postganglionic neurons thereof.The whole of the CSC, SCG and postganglionic neurons thereof go to formthe CSC-SCG complex (or CSC-SCG).

The inventors identified that the CSC-SCG complex is well placed tomodulate a variety of physiological functions playing important roles insleep apnoea. As demonstrated herein, stimulation of the CSC-SCG complexunilaterally (right or left) or bilaterally is able to induceimprovements in a range of sleep apnoea associated functions, includingblood pressure, diaphragmatic muscle activity, genioglossus muscle(tongue) activity and position, airway resistance, and the frequency andduration of disordered apnoeic breaths. These effects are not observedfollowing hypoglossal nerve stimulation.

Moreover, it is identified herein that different physiological responsescan be induced depending on whether stimulation is unilateral (right),unilateral (left), or bilateral. Thus, advantageously, one range ofresponses can be induced by unilateral (left) stimulation, for example adecrease in blood pressure; a second range of responses can be inducedby unilateral (right) stimulation, for example a decrease in respiratoryrate/increase in tidal volume; and a third range of responses induced bybilateral stimulation, for example a decrease in blood pressure and adecrease in respiratory rate/increase in tidal volume. Similarly, it isdemonstrated herein that different physiological responses can beinduced depending on the nature of the signal (for example, for anelectrical signal, by varying the frequency and/or pulse duration). Forexample, different reductions in airway resistance and/or blood pressurecan be induced depending on the nature of the signal applied. Thisdifferentiation of effects allows the appropriate stimulation to bematched to the symptoms exhibited by the subject at any given time.

This disclosure describes an apparatus and/or system for the treatmentof sleep apnoea, as well as methods for treating sleep apnoea, in asubject.

The terms as used herein are given their conventional definition in theart as understood by the skilled person, unless otherwise defined below.In the case of any inconsistency or doubt, the definition as providedherein should take precedence.

As used herein, application of a signal may equate to the transfer ofenergy in a suitable form to carry out the intended effect of thesignal. That is, application of a signal to a nerve or nerves may equateto the transfer of energy to (or from) the nerve(s) to carry out theintended effect. For example, the energy transferred may be electrical,mechanical (including acoustic, such as ultrasound), electromagnetic(e.g. optical), magnetic or thermal energy. It is noted that applicationof a signal as used herein does not include a pharmaceuticalintervention.

As used herein, “neural interfacing element” is taken to mean anyelement (e.g., a “transducer”) for applying a signal to the nerve, forexample an electrode, diode, Peltier element or ultrasound transducer.

As used herein, “neural activity” of a nerve is taken to mean thesignalling activity of the nerve, for example the amplitude, frequencyand/or pattern of action potentials in the nerve. “Sympathetic activity”is taken to mean signalling activity in a sympathetic nerve. “Localizedsympathetic activity” is sympathetic activity local to the nerve inwhich activity is stimulated—sympathetic activity in the stimulatednerve and those neurons downstream of the stimulated nerve. For example,localized sympathetic activity following stimulation of the CSC caninclude sympathetic activity in the CSC and also in the SCG and/or apostganglionic neuron thereof.

Modulation of neural activity, as used herein, is taken to mean that thesignalling activity of the nerve is altered from the baseline neuralactivity—that is, the signalling activity of the nerve in the subjectprior to any intervention. Such modulation may increase (i.e.stimulate), inhibit (for example block), or otherwise change the neuralactivity compared to baseline activity. In preferred embodiments of theinvention, the modulation is stimulation of neural activity, inparticular sympathetic activity.

Stimulation of neural activity (for example stimulation of sympatheticactivity) is an increase in neural activity, this may be an increase inthe total signalling activity of the whole nerve, or that the totalsignalling activity of a subset of nerve fibres of the nerve isincreased, compared to baseline neural activity in that part of thenerve.

Modulation of neural activity may also be an alteration in the patternof action potentials. It will be appreciated that the pattern of actionpotentials can be modulated without necessarily changing the overallfrequency or amplitude. For example, modulation of the neural activitymay be such that the pattern of action potentials is altered to moreclosely resemble a healthy state rather than a disease state.

Modulation of neural activity may comprise altering the neural activityin various other ways, for example increasing or inhibiting a particularpart of the neural activity and/or stimulating new elements of activity,for example in particular intervals of time, in particular frequencybands, according to particular patterns and so forth. Such altering ofneural activity may for example represent both increases and/ordecreases with respect to the baseline activity.

Modulation of the neural activity may be temporary. As used herein,“temporary” is taken to mean that the modulated neural activity (whetherthat is an increase, inhibition, block or other modulation of neuralactivity or change in pattern versus baseline activity) is notpermanent. That is, the neural activity following cessation of thesignal is substantially the same as the neural activity prior to thesignal being applied—i.e. prior to modulation.

Modulation of the neural activity may be persistent. As used herein,“persistent” is taken to mean that the modulated neural activity(whether that is an increase, inhibition, block or other modulation ofneural activity or change in pattern versus baseline activity) has aprolonged effect. That is, upon cessation of the signal, neural activityin the nerve remains substantially the same as when the signal was beingapplied—i.e. the neural activity during and following modulation issubstantially the same.

Modulation of the neural activity may be corrective. As used herein,“corrective” is taken to mean that the modulated neural activity(whether that is an increase, inhibition, block or other modulation ofneural activity or change in pattern versus baseline activity) altersthe neural activity towards the pattern of neural activity in a healthyindividual. That is, upon cessation of the signal, neural activity inthe nerve more closely resembles the pattern of action potentials in thenerve observed in a healthy subject than prior to modulation, preferablysubstantially fully resembles the pattern of action potentials in thenerve observed in a healthy subject.

Such corrective modulation caused by the signal can be any modulation asdefined herein. For example, application of the signal may result in ablock on neural activity, and upon cessation of the signal, the patternof action potentials in the nerve resembles the pattern of actionpotentials observed in a healthy subject. By way of further example,application of the signal may result in modulation such that the neuralactivity resembles the pattern of action potentials observed in ahealthy subject, and upon cessation of the signal, the pattern of actionpotentials in the nerve resembles the pattern of action potentialsobserved in a healthy individual.

As used herein, sleep apnoea (or sleep apnea) is used to refer todisorders characterised by interruptions in breathing during sleepand/or by shallow or infrequent breathing. “Sleep apnoea” is used torefer to both central sleep apnoea (CSA) and obstructive sleep apnoea(OSA) unless specified otherwise. An “apnoeic episode” is taken to meana single disordered breath or interruption in breathing. Risk factorsfor sleep apnoea include (but are not limited to) obesity, smoking,nasopharyngeal anatomical abnormalities, neck size greater than 16inches.

As used herein, the neural activity in the CSC-SCG (or a componentthereof) of a healthy individual is that neural activity exhibited by asubject who does not have sleep apnoea.

As used herein, an “improvement in a measurable physiological parameter”is taken to mean that for any given physiological parameter, animprovement is a change in the value of that parameter in the subjecttowards the normal value or normal range for that value—i.e. towards theexpected value in a healthy individual.

For an example, in a subject suffering from sleep apnoea, an improvementin measurable parameter may be one or more of: a decrease in systemicsympathetic tone, a decrease in duration of apnoeic episodes, a decreasein frequency of apnoeic episodes, a decrease in blood pressure (forexample a decrease in mean arterial pressure), a decrease in respiratoryrate, an increase in tidal volume, a decrease in upper airwayresistance, an increase in diaphragmatic muscle activity (also referredto as diaphragmatic tone), an increase in genioglossus muscle activity(also referred to as genioglossus tone), an increase in centralrespiratory drive.

Techniques for measuring these parameters would be familiar to theskilled person. For example: systemic sympathetic tone can be determinedby direct measurement of sympathetic nerve activity, by measurement oflevels of urinary catecholamines, measurement of the sympatho-vagalbalance via heart rate variability (lower heart rate variability beingindicative of a decrease in sympathetic tone); frequency and duration ofapnoeas can be determined during apnoeic sleep studies or by changes inchest wall impedence; blood pressure can be measured using invasivemethods (e.g. arterial blood pressure) or non-invasive methods (e.g.blood pressure cuffs, sphygmomanometers); respiratory parameters (e.g.respiratory rate, respiratory drive, tidal volume, minute ventilation,peak inspiratory/expiratory flow, inspiration/expiration time, EF₅₀) canbe measured by plethysmography; airway resistance can be determinedusing an airway perturbation device, a forced oscillation technique or aplethysmography device, or by end tidal CO₂; diaphragmatic muscleactivity can be determined using an implanted EMG electrode;genioglossus muscle activity can be determined during sleep endoscopy orby EMG in anaesthetised subjects.

The physiological parameter may comprise an action potential or patternof action potentials in a nerve of the subject. An improvement in such aparameter is characterised by the action potential or pattern of actionpotentials in the nerve more closely resembling that exhibited by ahealthy individual than before the intervention.

As used herein, a physiological parameter is not affected by modulationof the neural activity if the parameter does not change as a result ofthe modulation from the average value of that parameter exhibited by thesubject or patient when no intervention has been performed—i.e. it doesnot depart from the baseline value for that parameter.

The skilled person will appreciate that the baseline for any neuralactivity or physiological parameter in an individual need not be a fixedor specific value, but rather can fluctuate within a normal range or maybe an average value with associated error and confidence intervals.Suitable methods for determining baseline values would be well known tothe skilled person.

As used herein, a measurable physiological parameter is detected in asubject when the value for that parameter exhibited by the subject atthe time of detection is determined. A detector is any element able tomake such a determination.

A “predefined threshold value” for a physiological parameter is thevalue for that parameter where that value or beyond must be exhibited bya subject or patient before the intervention is applied. For any givenparameter, the threshold value may be a value indicative ofpredisposition to sleep apnoea, and/or an imminent or ongoing episode ofapnoea. Examples of such predefined threshold values include sympathetictone (neural, hemodynamic (e.g. heart rate, blood pressure, heart ratevariability) or circulating plasma/urine biomarkers) greater than athreshold sympathetic tone, or greater than sympathetic tone in ahealthy individual; diaphragmatic tone lower than a thresholddiaphragmatic tone, or greater than diaphragmatic tone in a healthyindividual; genioglossus tone lower than a threshold genioglossus tone,or greater than genioglossus tone in a healthy individual; bloodpressure higher than that characteristic of a healthy individual; arespiratory rate higher than that characteristic of a healthyindividual; a respiratory rate lower than that characteristic of ahealthy individual; a central respiratory drive lower than thatcharacteristic of a healthy individual; a tidal volume lower than thatcharacteristic of a healthy individual; an upper airway resistancehigher than that characteristic of a healthy individual. Appropriatevalues for any given parameter would be simply determined by the skilledperson.

Such a threshold value for a given physiological parameter is exceededif the value exhibited by the subject is beyond the threshold value—thatis, the exhibited value is a greater departure from the normal orhealthy value for that parameter than the predefined threshold value.

Treatment of sleep apnoea as used herein, for example treatment of CSAand/or treatment of OSA, is characterised by the subject exhibiting lessfrequent or less severe episodes of sleep apnoea than before treatment.Treatment may be characterised by amelioration of an ongoing apnoeicepisode. For example, treatment may be applied when the subject isundergoing an apnoeic episode and results in at least partial relief ofthe apnoeic episode, preferably full relief of the apnoeic episode (i.e.a return to healthy breathing pattern). Treatment may be indicated byone or more of: a decrease in duration of apnoeic episodes, a decreasein frequency of apnoeic episodes, a decrease in blood pressure (forexample a decrease in mean arterial pressure), a decrease in respiratoryrate, an increase in tidal volume, a decrease in upper airwayresistance, an increase in diaphragmatic muscle activity (also referredto as diaphragmatic tone), an increase in genioglossus muscle activity(also referred to as genioglossus tone).

A “neuromodulation device” or “neuromodulation apparatus” (usedinterchangeably) as used herein is a device or apparatus configured tomodulate the neural activity of a nerve. Neuromodulation devices asdescribed herein comprise at least one transducer capable of effectivelyapplying a signal to a nerve. In those embodiments in which theneuromodulation device is at least partially implanted in the subject,the elements of the device that are to be implanted in the subject areconstructed such that they are suitable for such implantation. Suchsuitable constructions would be well known to the skilled person.Indeed, various fully implantable neuromodulation devices are currentlyavailable, such as the vagus nerve stimulator of SetPoint Medical, inclinical development for the treatment of rheumatoid arthritis(Arthritis & Rheumatism, Volume 64, No. 10 (Supplement), page S195(Abstract No. 451), October 2012. “Pilot Study of Stimulation of theCholinergic Anti-Inflammatory Pathway with an Implantable Vagus NerveStimulation Device in Subjects with Rheumatoid Arthritis”, Frieda A.Koopman et al), and the INTERSTIM™ device (Medtronic, Inc), a fullyimplantable device utilised for sacral nerve modulation in the treatmentof overactive bladder.

As used herein, “implanted” is taken to mean positioned at leastpartially within the subject's body. Partial implantation means thatonly part of the device is implanted—i.e. only part of the device ispositioned within the subject's body, with other elements of the deviceexternal to the subject's body. Wholly implanted means that the entireof the device is positioned within the subject's body. For the avoidanceof doubt, the apparatus being “wholly implanted” does not precludeadditional elements, independent of the apparatus but in practice usefulfor its functioning (for example, a remote wireless charging unit or aremote wireless manual override unit), being independently formed andexternal to the subject's body. “Implantable” is taken to mean suitablefor such implantation.

As used herein, “charge-balanced” in relation to a DC current is takento mean that the positive or negative charge introduced into any system(e.g. a nerve) as a result of a DC current being applied is balanced bythe introduction of the opposite charge in order to achieve overall(i.e. net) neutrality.

As shown herein, it has been identified that sleep apnoea can be treatedby stimulation of the cervical sympathetic chain (CSC), superiorcervical ganglion (SCG) and/or a postganglionic branch thereof. Inaddition, it has been identified that stimulation of the CSC, SCG and/ora postganglionic branch thereof is able to induce changes in skeletalmuscle activity (specifically genioglossus and diaphragm muscleactivity), unusually for sympathetic nerve stimulation. Malposition ofthe tongue (controlled by the genioglossus) is heavily involved in bothCSA and OSA. Therefore, such changes in skeletal muscle activity providefurther means of treating sleep apnoea by reducing or preventing theanatomical causes of sleep apnoea.

Further surprisingly, it has been identified that different aspects ofsleep apnoea can be treated via differential unilateral stimulation andbilateral stimulation. That is, stimulation of the left CSC-SCG (or acomponent thereof) can induce improvements in one set of sleep apnoeasymptoms (for example, reducing blood pressure), stimulation of theright CSC-SCG (or a component thereof) can induce improvements inanother set of sleep apnoea symptoms (for example reducing respiratoryrate/increasing tidal volume), and bilateral stimulation can induceimprovements across both sets of sleep apnoea symptoms. Similarly, it isdemonstrated herein that different physiological responses can beinduced depending on the nature of the signal applied (for example, foran electrical signal, by varying the frequency and/or pulse duration).For example, different reductions in airway resistance and/or bloodpressure can be induced depending on the nature of the signal applied.

Such differential effects will allow for targeted and specific treatmentof whichever symptoms are being exhibited by a given subject, at a giventime.

A neuromodulation device that stimulates the neural activity in a CSC,SCG and/or a postganglionic branch thereof of a subject will thereforeprovide an effective treatment for sleep apnoea.

Therefore, in accordance with one aspect of the invention there isprovided an apparatus or system for increasing the neural activity of aCSC, SCG and/or postganglionic branch thereof of a subject, theapparatus comprising: a transducer configured to apply a signal to thenerve, optionally at least two such transducers; and a controlleroperably coupled to the transducer or transducers, the controllercontrolling the signal to be applied by each transducer, such that thesignal modulates the neural activity of the nerve. In certain preferredembodiments, the signal stimulates localized sympathetic activity in theCSC, SCG and/or postganglionic neurons thereof. This stimulation insympathetic activity produces a physiological response in the subject,for example one or more of: a decrease in blood pressure, a decrease inrespiratory rate, an increase in tidal volume, a decrease in upperairway resistance, an increase in diaphragmatic muscle activity, anincrease in genioglossus muscle activity, an increase in centralrespiratory drive. Thus, in a related aspect, the apparatus or system isprovided for treating sleep apnoea in a subject, such as a patientexperiencing or suffering from sleep apnoea.

In certain such embodiments, the signal applied by the one or moretransducers is an electrical signal, an optical signal, an ultrasonicsignal, or a thermal signal. In those embodiments in which the apparatushas at least two transducers, the signal which each of the transducersis configured to apply is independently selected from an electricalsignal, an optical signal, an ultrasonic signal, and a thermal signal.That is, each transducer may be configured to apply a different signal.Alternatively, in certain embodiments each transducer is configured toapply the same signal.

In certain embodiments, each transducer may be comprised of one or moreelectrodes, one or more photon sources, one or more ultrasoundtransducers, one more sources of heat, or one or more other types oftransducer arranged to put the signal into effect.

In certain embodiments, the signal applied is an electrical signal, forexample a voltage or current. In certain such embodiments the signalapplied comprises a direct current (DC) waveform, such as a chargebalanced direct current waveform, or an alternating current (AC)waveform, or both a DC and an AC waveform.

In certain embodiments, the DC waveform or AC waveform may be a square,sinusoidal, triangular or complex waveform. The DC waveform mayalternatively be a constant amplitude waveform.

It will be appreciated by the skilled person that the current amplitudeof an applied electrical signal necessary to achieve the intendedstimulation will depend upon the positioning of the electrode and theassociated electrophysiological characteristics (e.g. impedance). It iswithin the ability of the skilled person to determine the appropriatecurrent amplitude for achieving the intended stimulation in a givensubject. For example, the skilled person is aware of methods suitable tomonitor the neural activity profile induced by neuronal or nervestimulation.

In certain embodiments, wherein the signal comprises an AC waveformand/or a DC waveform, each waveform has an independently selectedfrequency of 0.5-100 Hz, optionally 1-50 Hz, optionally of 1-25 Hz,optionally 1-10 Hz. In certain embodiments, the signal has a frequencyof 1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, 3 Hz, 3.5 Hz, 4 Hz, 4.5 Hz, 5 Hz, 5.5 Hz,6 Hz, 6.5 Hz, 7 Hz, 7.5 Hz, 8 Hz, 8.5 Hz, 9 Hz, 9.5 Hz, 10 Hz, 15 Hz, 20Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, 50 Hz. In certain embodiments,the signal is an electrical signal having a frequency of 7.5 Hz. It willbe appreciated by those of skill in the art that the lower and upperlimits of such ranges can vary independently, such that the signal canhave a frequency of at least 1 Hz, or at least 2.5 Hz, or at least 5 Hz,or at least 10 Hz, or at least 20 Hz, or at least 25 Hz, or at least 50Hz, or at least 100 Hz. Such a signal can have a frequency less than 1kHz, or 500 Hz, or 200 Hz, or 100 Hz, or 50 Hz or 20 Hz, or 10 Hz.

In certain embodiments, the signal is an electrical signal and isinitiated at a first frequency and then altered to a second frequency,wherein (a) the first frequency is higher than the second frequency; or(b) the first frequency is lower than the second frequency.

In certain embodiments, the signal is an electrical signal having avoltage of 1-20V. In certain preferred embodiments, the signal has avoltage of 5-15V, optionally 10-15V. In certain preferred embodimentsthe voltage is selected from 5V, 10V and 15V. It will be appreciated bythose of skill in the art that the lower and upper limits of such rangescan vary independently.

In certain embodiments, the signal is an electrical signal having acurrent of 0.1-5 mA, optionally 0.5-2 mA, optionally 0.75-1.5 mA,optionally 0.8-1 mA. In certain embodiments, the signal is an electricalsignal having a current of at least 0.1 mA, at least 0.2 mA, at least0.3 mA, at least 0.4 mA, at least 0.5 mA, at least 0.6 mA, at least 0.7mA, at least 0.8 mA, at least 0.9 mA, at least 1.0 mA. It will beappreciated by those of skill in the art that the lower and upper limitsof such ranges can vary independently, such that the signal can have acurrent of at least 0.1 mA, or at least 0.2 mA, or at least 0.3 mA, orat least 0.4 mA, or at least 0.5 mA, or at least 0.8 mA. Such a signalcan have a current less than 5 mA, or 2 mA, or 1.5 mA, or 1 mA, or 0.8mA. In certain preferred embodiments the signal has a current of lessthan 0.8 mA.

In certain embodiments the signal is an electrical signal having a pulsewidth of 0.05-5 ms, 0.1-5 ms, optionally 0.5-5 ms, optionally 1-3 ms,optionally 2 ms. In certain embodiments, the signal is an electricalsignal having a pulse width of 0.2-5 ms. In certain embodiments, thesignal has a pulse width of 0.1 ms, or 0.2 ms, or 0.5 ms, or 1 ms. Itwill be appreciated by those of skill in the art that the lower andupper limits of such ranges can vary independently, such that the signalcan have a pulse duration of at least 0.05 ms, 0.1 ms, 0.2 ms, 0.5 ms, 1ms or 2 ms. Such a signal can have a pulse duration less than 5 ms, 3ms, 2 ms, 1 ms, 0.5 ms, 0.2 ms, or 0.1 ms.

In certain preferred embodiments, the signal comprises an AC waveform of7.5 Hz 0.8 mA, or an AC waveform of 7.5 Hz 1 mA, or an AC waveform of7.5 Hz 10V. In certain preferred embodiments, the signal comprises an ACwaveform, has a current of at least 0.8 mA, has a pulse duration of 2ms, and has a frequency selected from 2.5 Hz, 5 Hz, 7.5 Hz, 10 Hz, 20 Hzor 50 Hz. In certain preferred embodiments, the signal comprises an ACwaveform, has a current of at least 0.5 mA, has a frequency of 5 Hz, andhas a pulse duration selected from 0.1 ms, 0.2 ms, 0.5 ms, 1 ms or 2 ms.

In those embodiments in which the signal applied is an electricalsignal, each transducer configured to apply the electrical signal is anelectrode, for example a cuff or wire electrode. In certain suchembodiments, all the transducers are electrodes configured to apply anelectrical signal, optionally the same electrical signal.

In certain embodiments wherein the signal applied by the one or moretransducers is a thermal signal, the signal reduces the temperature ofthe nerve (i.e. cools the nerve). In certain alternative embodiments,the signal increases the temperature of the nerve (i.e. heats thenerve). In certain embodiments, the signal both heats and cools thenerve.

In those embodiments in which the signal applied by the one or moretransducers is a thermal signal, at least one of the one or moretransducers is a transducer configured to apply a thermal signal. Incertain such embodiments, all the transducers are configured to apply athermal signal, optionally the same thermal signal.

In certain embodiments, one or more of the one or more transducerscomprise a Peltier element configured to apply a thermal signal,optionally all of the one or more transducers comprise a Peltierelement. In certain embodiments, one or more of the one or moretransducers comprise a laser diode configured to apply a thermal signal,optionally all of the one or more transducers comprise a laser diodeconfigured to apply a thermal signal. In certain embodiments, one ormore of the one or more transducers comprise a electrically resistiveelement configured to apply a thermal signal, optionally all of the oneor more transducers comprise a electrically resistive element configuredto apply a thermal signal.

In certain embodiments the signal applied by the one or more transducersis a mechanical signal, optionally an ultrasonic signal. In certainalternative embodiments, the mechanical signal applied by the one ormore transducers is a pressure signal.

In certain embodiments the signal applied by the one or more transducersis an electromagnetic signal, optionally an optical signal. In certainsuch embodiments, the one or more transducers comprise a laser and/or alight emitting diode configured to apply the optical signal.

In certain embodiments, the physiological response produced in thesubject is one or more of: an decrease in systemic sympathetic tone, adecrease in duration of apnoeic episodes, a decrease in frequency ofapnoeic episodes, a decrease in blood pressure (for example a decreasein mean arterial pressure), a decrease in respiratory rate, an increasein tidal volume, a decrease in upper airway resistance, an increase indiaphragmatic muscle activity (also referred to as diaphragmatic tone),an increase in genioglossus muscle activity (also referred to asgenioglossus tone), an increase in central respiratory drive.

In certain embodiments, the apparatus further comprises a detectorelement to detect one or more physiological parameters in the subject.Such a detector element may be configured to detect the one or morephysiological parameters. That is, in such embodiments each detector maydetect more than one physiological parameter, for example all thedetected physiological parameters. Alternatively, in such embodimentseach of the one or more detector elements is configured to detect aseparate parameter of the one or more physiological parameters detected.

In such embodiments, the controller is coupled to the detector elementconfigured to detect one or more physiological parameters, and causesthe transducer or transducers to apply the signal when the physiologicalparameter is detected to be meeting or exceeding a predefined thresholdvalue.

In certain embodiments, the one or more detected physiologicalparameters are selected from: systemic sympathetic tone; diaphragmatictone; genioglossus tone; blood pressure; respiratory rate; tidal volume;upper airway resistance.

In certain embodiments, the one or more detected physiologicalparameters comprise an action potential or pattern of action potentialsin a nerve of the subject, wherein the action potential or pattern ofaction potentials is associated with sleep apnoea. In certain suchembodiments, the nerve is part of the cervical sympathetic chain. Incertain such embodiments, the nerve is a superior cervical ganglion or apostganglionic branch thereof.

It will be appreciated that any two or more of the indicatedphysiological parameters may be detected in parallel or consecutively.For example, in certain embodiments, the controller is coupled to adetector or detectors configured to detect the pattern of actionpotentials in a superior cervical ganglion and also to detect the bloodpressure of the subject.

Application of the signal by an apparatus according to the inventioncauses an increase in neural activity in the nerve or nerves to whichthe signal is applied. That is, in such embodiments, application of thesignal results in the neural activity in at least part of the nerve ornerves being increased compared to the baseline neural activity in thatpart of the nerve. Such an increase in activity could equally be acrossthe whole nerve, in which case neural activity would be increased acrossthe whole nerve or nerves. Therefore, in certain such embodiments, aresult of applying the signal is an increase in neural activity in thenerve or nerves. In certain embodiments, a result of applying the signalis an increase in neural activity across the whole nerve or nerves.

In certain embodiments, neural activity may be further modulated as aresult of applying the signal, for example resulting in an alteration tothe pattern of action potentials in the nerve or nerves. In certain suchembodiments, the neural activity is modulated such that the resultantpattern of action potentials in the nerve or nerves resembles thepattern of action potentials in the nerve or nerves observed in ahealthy subject. Such modulation may comprise altering the neuralactivity in various other ways, for example increasing or inhibiting aparticular part of the activity and stimulating new elements ofactivity, for example in particular intervals of time, in particularfrequency bands, according to particular patterns and so forth.

In certain embodiments, the controller causes the signal to be appliedintermittently. In certain such embodiments, the controller causes thesignal to applied for a first time period, then stopped for a secondtime period, then reapplied for a third time period, then stopped for afourth time period. In such an embodiment, the first, second, third andfourth periods run sequentially and consecutively. The series of first,second, third and fourth periods amounts to one application cycle. Incertain such embodiments, multiple application cycles can runconsecutively such that the signal is applied in phases, between whichphases no signal is applied.

In certain embodiments, the application cycles are not immediatelyconsecutive. In certain such embodiments the application cycles areseparated by a period of 1-60 min, 5-30 min, 10-20 min, optionally 15min.

In such embodiments, the duration of the first, second, third and fourthtime periods is independently selected. That is, the duration of eachtime period may be the same or different to any of the other timeperiods. In certain such embodiments, the duration of each of the first,second, third and fourth time periods is any time from 5 seconds (5 s)to 24 hours (24 h), 30 s to 12 h, 1 min to 12 h, 5 min to 8 h, 5 min to6 h, 10 min to 6 h, 10 min to 4 h, 30 min to 4 h, 1 h to 4 h. In certainembodiments, the duration of each of the first, second, third and fourthtime periods is independently selected from: 0.8 s-2 min, 0.8 s-30 s,0.8 s-10 s, 0.8 s-5 s, 0.8-2 s, 10 s-2 min, 30 s-2 min, 30 s-1 min,optionally 30 s. In certain embodiments, the duration of each of thefirst, second, third and fourth time periods is 5 s, 10 s, 30 s, 60 s, 2min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 2 h,3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h,16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h. In certainembodiments, the first and third periods are not 3 minutes and thesecond and fourth periods are not 10 minutes.

In certain embodiments, immediately consecutive application cycles areapplied for an operative period—that is, an operative period is a periodover which consecutive application cycles are in operation. In suchembodiments, the operative period is immediately followed by aninoperative period. In certain embodiments, the operative andinoperative period have a duration independently selected from 1-60 min,5-30 min, 10-20 min, optionally 15 min. In certain embodiments, theoperative and inoperative period have a duration independently selectedfrom 1-24 h, 1-12 h, 1-6 h, optionally 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h,20 h, 21 h, 22 h, 23 h, 24 h.

In certain embodiments wherein the controller causes the signal to beapplied intermittently, the signal is applied for a specific amount oftime per day. In certain such embodiments, the signal is applied for 10min, 20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h,6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18h, 19 h, 20 h, 21 h, 22 h, 23 h per day. In certain such embodiments,the signal is applied continuously for the specified amount of time. Incertain alternative such embodiments, the signal may be applieddiscontinuously across the day, provided the total time of applicationamounts to the specified time.

In certain embodiments wherein the controller causes the signal to beapplied intermittently, the signal is applied only when the subject isin a specific physiological state. For example, in certain embodiments,the signal may be applied only when the subject is asleep, and/or onlywhen the subject is undergoing an apnoeic episode.

In certain such embodiments, the apparatus further comprises acommunication, or input, element via which the status of the subject(e.g. that they are going to sleep) can be indicated by the subject or aphysician. In alternative embodiments, the apparatus further comprises adetector configured to detect the status of the subject, wherein thesignal is applied only when the detector detects that the subject is inthe specific state.

In certain embodiments, the detector detects that the subject or patientis undergoing an apnoeic episode characterised by one or morephysiological parameters being at or beyond the threshold value for eachparameter. In response, the controller causes a signal to be appliedeither bilaterally, unilaterally (right) or unilaterally (left),depending on which parameters characterise the apnoeic episode. Forexample, if the apnoeic episode is characterised predominantly by adetected increase in blood pressure, the controller might cause thesignal to be applied unilaterally to the left CSC-SCG (or a componentthereof). By way of further example, if the apnoeic episode ischaracterised predominantly by a detected increase in respiratoryrate/decrease in tidal volume, the controller might cause the signal tobe applied unilaterally to the right CSC-SCG (or a component thereof).By way of yet further example, if the apnoeic episode is characterisedpredominantly by an increase in blood pressure and a detected increasein respiratory rate/decrease in tidal volume, the controller might causethe signal to be applied bilaterally in order to treat allcharacterising parameters of the apnoeic episode.

In certain alternative embodiments, the controller causes the signal tobe permanently applied. That is, once begun, the signal is continuouslyapplied to the nerve or nerves. It will be appreciated that inembodiments wherein the signal is a series of pulses, gaps betweenpulses do not mean the signal is not continuously applied.

In certain embodiments of the apparatus, the modulation in neuralactivity caused by the application of the signal is temporary. That is,upon cessation of the signal, neural activity in the nerve or nervesreturns substantially towards baseline neural activity within 1-60seconds, or within 1-60 minutes, or within 1-24 hours, optionally 1-12hours, optionally 1-6 hours, optionally 1-4 hours, optionally 1-2 hours.In certain such embodiments, the neural activity returns substantiallyfully to baseline neural activity. That is, the neural activityfollowing cessation of the signal is substantially the same as theneural activity prior to the signal being applied—i.e. prior tostimulation.

In certain alternative embodiments, the increase in neural activitycaused by the application of the signal or signals is substantiallypersistent. That is, upon cessation of the signal, neural activity inthe nerve or nerves remains substantially the same as when the signalwas being applied—i.e. the neural activity during and followingstimulation is substantially the same.

In certain embodiments, the increase in neural activity caused by theapplication of the signal is partially corrective, preferablysubstantially corrective. That is, upon cessation of the signal, neuralactivity in the nerve or nerves more closely resembles the pattern ofaction potentials in the nerve(s) observed in a healthy subject thanprior to stimulation, preferably substantially fully resembles thepattern of action potentials in the nerve(s) observed in a healthysubject. For example, application of the signal may result in anincrease in neural activity, and upon cessation of the signal, thepattern of action potentials in the nerve or nerves resembles thepattern of action potentials observed in a healthy individual. It ishypothesised that such a corrective effect is the result of a positivefeedback loop—that is, the underlying predisposition to sleep apnoea istreated as result of the stimulation caused by application of thesignal.

In certain embodiments, the apparatus is suitable for at least partialimplantation into the subject. In certain such embodiments, theapparatus is suitable to be fully implanted in the subject. For theavoidance of doubt, the apparatus being “wholly implanted” does notpreclude additional elements, independent of the apparatus but inpractice useful for its functioning (for example, a remote wirelesscharging unit or a remote wireless manual override unit), beingindependently formed and external to the subject's body.

In certain embodiments, the apparatus further comprises one or morepower supply elements, for example a battery, and/or one or morecommunication elements.

In another aspect, the invention provides a method of treating sleepapnoea (OSA and/or CSA), the method comprising implanting an apparatusaccording to the first aspect, positioning at least one transducer ofthe apparatus in signalling contact with a CSC, SCG and/orpostganglionic branch thereof of a subject, and activating theapparatus. In such embodiments, the transducer is in signalling contactwith the nerve when it is positioned such that the signal can beeffectively applied to the nerve. The apparatus is activated when theapparatus is in an operating state such that the signal will be appliedas determined by the controller.

In certain such embodiments, a first transducer is positioned insignalling contact with a left CSC, SCG and/or postganglionic branch ofsaid subject to stimulate the neural activity of said left CSC, SCGand/or postganglionic branch in the subject, and a second transducer ispositioned in signalling contact with a right CSC, SCG and/orpostganglionic branch of said subject to stimulate the neural activityof said right CSC, SCG and/or postganglionic branch in the subject. Incertain such embodiments, the first and second transducers are part ofone apparatus according to the first aspect. In alternative suchembodiments, the first and second transducers are part of separateapparatuses according to the first aspect.

Implementation of all aspects of the invention (as discussed both aboveand below) will be further appreciated by reference to FIGS. 3A-3C.

FIGS. 3A-3C show how the invention may be put into effect using one ormore neuromodulation devices which are implanted in, located on, orotherwise disposed with respect to a subject in order to carry out anyof the various methods described herein. In this way, one or moreneuromodulation apparatuses can be used to treat sleep apnoea in asubject, by stimulating neural activity in a CSC, SCG and/orpostganglionic branch thereof of the subject.

In each of the FIGS. 3B-3C a separate neuromodulation device 100 isprovided in respect of each of the left and right CSC-SCG complex,although as discussed herein a device could be provided or used inrespect of only one of the CSC-SCG complex. As described herein, thedevice could be provided or used in relation to any one or more elementsof the CSC-SCG complex (e.g. the CSC, SCG and/or a postganglionic branchthereof). Each such neuromodulation device may be fully or partiallyimplanted in the subject, or otherwise located, so as to provideneuromodulation of the respective nerve or nerves. Each of the left andright neuromodulation devices 100 may operate independently, or mayoperate in communication with each other.

FIG. 3A also shows schematically components of an implantedneuromodulation device 100, in which the device comprises severalelements, components or functions grouped together in a single unit andimplanted in the subject. A first such element is a transducer 102 whichis shown in proximity to a CSC, SCG or postganglionic neuron thereof 90of the subject. The transducer 102 may be operated by a controllerelement 104. The device may comprise one or more further elements suchas a communication element 106, a detector element 108, a power supplyelement 110 and so forth.

Each neuromodulation device 100 may carry out the requiredneuromodulation independently, or in response to one or more controlsignals. Such a control signal may be provided by the controller element104 according to an algorithm, in response to output of one or moredetector elements 108, and/or in response to communications from one ormore external sources received using the communications element. Asdiscussed herein, the detector element(s) could be responsive to avariety of different physiological parameters, as described below.

FIG. 3B illustrates some ways in which the apparatus of FIG. 2A may bedifferently distributed. For example, in FIG. 3B the neuromodulationdevices 100 comprise transducers 102 implanted proximally to a CSC, SCGor postganglionic branch 90, but other elements such as a controllerelement 104, a communication element 106 and a power supply 110 areimplemented in a separate control unit 130 which may also be implantedin, or carried by the subject. The control unit 130 then controls thetransducers in both of the neuromodulation devices via connections 132which may for example comprise electrical wires and/or optical fibresfor delivering signals and/or power to the transducers.

In the arrangement of FIG. 3B one or more detector elements 108 arelocated separately from the control unit, although one or more suchdetector elements could also or instead be located within the controlunit 130 and/or in one or both of the neuromodulation devices 100. Thedetector elements may be used to detect one or more physiologicalparameters of the subject, and the controller element or control unitthen causes the transducers to apply the signal in response to thedetected parameter(s), for example only when a detected physiologicalparameter meets or exceeds a predefined threshold value. Physiologicalparameters which could be detected for such purposes include one or moreof: sympathetic tone; diaphragmatic tone; genioglossus tone; bloodpressure; respiratory rate; tidal volume; upper airway resistance;central respiratory drive. Similarly, a detected physiological parametercould be an action potential or pattern of action potentials in a nerveof the subject, for example a CSC, SCG and/or postganglionic branch,wherein the action potential or pattern of action potentials isassociated with sleep apnoea.

As already described, in arrangements such as those of FIG. 3B or 3C,detector elements may be used to detect physiological parameters thatcharacterise a particular apnoeic episode. In response, the controllerelement or control unit can cause the transducers to apply the signalbilaterally, unilaterally (left) or unilaterally (right), depending onthe parameters characterising the particular apnoeic episode. Forexample, if the apnoeic episode is characterised predominantly by adetected increase in blood pressure, the controller element might causethe signal to be applied unilaterally to the left CSC-SCG (or acomponent thereof). By way of further example, if the apnoeic episode ischaracterised predominantly by a detected increase in respiratoryrate/decrease in tidal volume, the controller element might cause thesignal to be applied unilaterally to the right CSC-SCG (or a componentthereof). By way of yet further example, if the apnoeic episode ischaracterised predominantly by an increase in blood pressure and adetected increase in respiratory rate/decrease in tidal volume, thecontroller element might cause the signal to be applied bilaterally inorder to treat all characterising parameters of the apnoeic episode.

A variety of other ways in which the various functional elements couldbe located and grouped into the neuromodulation devices, a control unit130 and elsewhere are of course possible. For example, one or moresensors of FIG. 3B could be used in the arrangement of FIG. 3A or 3C orother arrangements.

FIG. 3C illustrates some ways in which some functionality of theapparatus of FIG. 3A or 3B is provided not implanted in the subject. Forexample, in FIG. 3C an external power supply 140 is provided which canprovide power to implanted elements of the apparatus in ways familiar tothe skilled person, and an external controller 150 provides part or allof the functionality of the controller element 104, and/or providesother aspects of control of the apparatus, and/or provides data readoutfrom the apparatus, and/or provides a data input facility 152. The datainput facility could be used by a subject or other operator in variousways, for example to input data relating to the status of the subject(e.g. if they are about to go to sleep).

Each neuromodulation device may be adapted to carry out theneuromodulation required using one or more physical modes of operationwhich typically involve applying a signal to a CSC, SCG and/orpostganglionic branch, such a signal typically involving a transfer ofenergy to (or from) the nerve(s). As already discussed, such modes maycomprise stimulating neural activity in the nerve or nerves using anelectrical signal, an optical signal, an ultrasound or other mechanicalsignal, a thermal signal, a magnetic or electromagnetic signal, or someother use of energy to carry out the required stimulation. To this end,the transducer 102 illustrated in FIG. 3A could be comprised of one ormore electrodes, one or more photon sources, one or more ultrasoundtransducers, one more sources of heat, or one or more other types oftransducer arranged to put the required neuromodulation into effect.

In certain embodiments, the signal applied is an electrical signal, forexample a voltage or current. In certain such embodiments the signalapplied comprises a direct current (DC) waveform, such as a chargebalanced direct current waveform, or an alternating current (AC)waveform, or both a DC and an AC waveform.

In certain embodiments, the DC waveform or AC waveform may be a square,sinusoidal, triangular or complex waveform. The DC waveform mayalternatively be a constant amplitude waveform.

It will be appreciated by the skilled person that the current/voltageamplitude of an applied electrical signal necessary to achieve theintended stimulation will depend upon the positioning of the electrodeand the associated electrophysiological characteristics (e.g.impedance). It is within the ability of the skilled person to determinethe appropriate current amplitude for achieving the intended stimulationin a given subject. For example, the skilled person is aware of methodssuitable to monitor the neural activity profile induced by neuronal ornerve stimulation.

In certain embodiments, wherein the signal comprises an AC waveformand/or a DC waveform, each waveform has an independently selectedfrequency of 0.5-100 Hz, optionally 1-50 Hz, optionally of 1-25 Hz,optionally 1-10 Hz. In certain embodiments, the signal has a frequencyof 1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, 3 Hz, 3.5 Hz, 4 Hz, 4.5 Hz, 5 Hz, 5.5 Hz,6 Hz, 6.5 Hz, 7 Hz, 7.5 Hz, 8 Hz, 8.5 Hz, 9 Hz, 9.5 Hz, 10 Hz, 15 Hz, 20Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, 50 Hz. In certain embodiments,the signal is an electrical signal having a frequency of 7.5 Hz. It willbe appreciated by those of skill in the art that the lower and upperlimits of such ranges can vary independently, such that the signal canhave a frequency of at least 1 Hz, or at least 2.5 Hz, or at least 5 Hz,or at least 10 Hz, or at least 20 Hz, or at least 25 Hz, or at least 50Hz, or at least 100 Hz. Such a signal can have a frequency less than 1kHz, or 500 Hz, or 200 Hz, or 100 Hz, or 50 Hz or 20 Hz, or 10 Hz.

In certain embodiments, the signal is an electrical signal and isinitiated at a first frequency and then altered to a second frequency,wherein (a) the first frequency is higher than the second frequency; or(b) the first frequency is lower than the second frequency.

In certain embodiments, the signal is an electrical signal having avoltage of 1-20V. In certain preferred embodiments, the signal has avoltage of 5-15V, optionally 10-15V. In certain preferred embodimentsthe voltage is selected from 5V, 10V and 15V.

In certain embodiments, the signal is an electrical signal having acurrent of 0.1-5 mA, optionally 0.5-2 mA, optionally 0.75-1.5 mA,optionally 0.8-1 mA. In certain embodiments, the signal is an electricalsignal having a current of at least 0.1 mA, at least 0.2 mA, at least0.3 mA, at least 0.4 mA, at least 0.5 mA, at least 0.6 mA, at least 0.7mA, at least 0.8 mA, at least 0.9 mA, at least 1.0 mA. It will beappreciated by those of skill in the art that the lower and upper limitsof such ranges can vary independently, such that the signal can have acurrent of at least 0.1 mA, or at least 0.2 mA, or at least 0.3 mA, orat least 0.4 mA, or at least 0.5 mA, or at least 0.8 mA. Such a signalcan have a current less than 5 mA, or 2 mA, or 1.5 mA, or 1 mA, or 0.8mA. In certain preferred embodiments the signal has a current of lessthan 0.8 mA.

In certain embodiments the signal is an electrical signal having a pulsewidth of 0.1-5 ms, optionally 0.5-5 ms, optionally 1-3 ms, optionally 2ms. In certain embodiments, the signal is an electrical signal having apulse width of 0.2-5 ms. In certain embodiments, the signal has a pulsewidth of 0.1 ms, or 0.2 ms, or 0.5 ms, or 1 ms. It will be appreciatedby those of skill in the art that the lower and upper limits of suchranges can vary independently, such that the signal can have a pulseduration of at least 0.05 ms, 0.1 ms, 0.2 ms, 0.5 ms, 1 ms or 2 ms. Sucha signal can have a pulse duration less than 5 ms, 3 ms, 2 ms, 1 ms, 0.5ms, 0.2 ms, or 0.1 ms.

In certain preferred embodiments, the signal comprises an AC waveform of7.5 Hz 0.8 mA, or an AC waveform of 7.5 Hz 1 mA, or an AC waveform of7.5 Hz 10V. In certain preferred embodiments, the signal comprises an ACwaveform, has a current of at least 0.8 mA, has a pulse duration of 2ms, and has a frequency selected from 2.5 Hz, 5 Hz, 7.5 Hz, 10 Hz, 20 Hzor 50 Hz. In certain preferred embodiments, the signal comprises an ACwaveform, has a current of at least 0.5 mA, has a frequency of 5 Hz, andhas a pulse duration selected from 0.1 ms, 0.2 ms, 0.5 ms, 1 ms or 2 ms.

In those embodiments in which the signal applied is an electricalsignal, each transducer configured to apply the electrical signal is anelectrode, for example a cuff or wire electrode. In certain suchembodiments, all the transducers are electrodes configured to apply anelectrical signal, optionally the same electrical signal.

In a third aspect, the invention provides a method of treating sleepapnoea, for example OSA and/or CSA, in a subject, the method comprisingapplying a signal to a part or all of a CSC, SCG and/or a postganglionicbranch thereof of said subject to stimulate the neural activity of saidCSC, SCG and/or postganglionic branch thereof in the subject.

In certain embodiments, the signal is applied by a neuromodulationdevice comprising one or more transducers configured to apply thesignal. In certain preferred embodiments the neuromodulation device isat least partially implanted in the subject. In certain preferredembodiments, the neuromodulation device is wholly implanted in thesubject. For the avoidance of doubt, the apparatus being “whollyimplanted” does not preclude additional elements, independent of theapparatus but in practice useful for its functioning (for example, aremote wireless charging unit or a remote wireless manual overrideunit), being independently formed and external to the subject's body.

In certain embodiments, the treatment of sleep apnoea is treatment ofCSA or treatment of OSA. In certain embodiments, the treatment ischaracterised by the subject exhibiting less frequent and/or less severeepisodes of sleep apnoea than before treatment. In certain embodiments,treatment may be characterised by amelioration of an ongoing apnoeicepisode.

In certain embodiments, treatment of sleep apnoea is indicated by animprovement in a measurable physiological parameter, for example one ormore of: a decrease in duration of apnoeic episodes, a decrease infrequency of apnoeic episodes, a decrease in blood pressure (for examplea decrease in mean arterial pressure), a decrease in respiratory rate,an increase in tidal volume, a decrease in upper airway resistance, anincrease in diaphragmatic muscle activity (also referred to asdiaphragmatic tone), an increase in genioglossus muscle activity (alsoreferred to as genioglossus tone), an increase in central respiratorydrive. Suitable methods for determining the value for any givenparameter would be appreciated by the skilled person and examples havebeen described above.

It will be appreciated that treatment of sleep apnoea, for example OSAand/or CSA, may include one or more or all of the above characteristics.That is, treatment of sleep apnoea according to the method may becharacterised by reduced blood pressure, and less frequent apnoeicepisodes, with any episode also being less severe than before treatment.

In certain embodiments, treatment of the condition is indicated by animprovement in the profile of neural activity in the nerve or nerves towhich the signal is applied. That is, treatment of the condition isindicated by the neural activity in the nerve(s) approaching the neuralactivity in a healthy individual—i.e. the pattern of action potentialsin the nerve more closely resembling that exhibited by a healthyindividual than before the intervention.

Stimulation of neural activity as a result of applying the signal is anincrease in neural activity in the nerve or nerves. That is, in suchembodiments, application of the signal results in the neural activity inat least part of the nerve(s) being increased compared to the baselineneural activity in that part of the nerve.

Neural activity may also be modulated as a result of applying the signalsuch that there is an alteration to the pattern of action potentials innerve or nerves to which a signal is applied. In certain suchembodiments, the neural activity is modulated such that the resultantpattern of action potentials in the nerve or nerves resembles thepattern of action potentials in the nerve(s) observed in a healthysubject.

In certain embodiments, the signal is applied intermittently. In certainsuch embodiments, the signal is applied for a first time period, thenstopped for a second time period, then reapplied for a third timeperiod, then stopped for a fourth time period. In such an embodiment,the first, second, third and fourth periods run sequentially andconsecutively. The series of first, second, third and fourth periodsamounts to one application cycle. In certain such embodiments, multipleapplication cycles can run consecutively such that the signal is appliedin phases, between which phases no signal is applied.

In certain embodiments, the application cycles are not immediatelyconsecutive. In certain such embodiments the application cycles areseparated by a period of 1-60 min, 5-30 min, 10-20 min, optionally 15min.

In such embodiments, the duration of the first, second, third and fourthtime periods is independently selected. That is, the duration of eachtime period may be the same or different to any of the other timeperiods. In certain embodiments, the first, second, third and fourthperiods are independently selected from: 0.8 s-2 min, 0.8 s-30 s, 0.8s-10 s, 0.8 s-5 s, 0.8-2 s, 10 s-2 min, 30 s-2 min, 30 s-1 min,optionally 30 s. In certain embodiments, the duration of each of thefirst, second, third and fourth time periods is any time from 5 seconds(5 s) to 24 hours (24 h), 30 s to 12 h, 1 min to 12 h, 5 min to 8 h, 5min to 6 h, 10 min to 6 h, 10 min to 4 h, 30 min to 4 h, 1 h to 4 h. Incertain embodiments, the duration of each of the first, second, thirdand fourth time periods is independently selected from 5 s, 10 s, 30 s,60 s, 2 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h. Incertain embodiments, the first and third periods are not 3 minutes andthe second and fourth periods are not 10 minutes.

In certain embodiments, immediately consecutive application cycles areapplied for an operative period—that is, an operative period is a periodover which consecutive application cycles are in operation. In suchembodiments, the operative period is immediately followed by aninoperative period. In certain embodiments, the operative andinoperative period have a duration independently selected from 1-60 min,5-30 min, 10-20 min, optionally 15 min. In certain embodiments, theoperative and inoperative period have a duration independently selectedfrom 1-24 h, 1-12 h, 1-6 h, optionally 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h,20 h, 21 h, 22 h, 23 h, 24 h.

In certain embodiments wherein the signal is applied intermittently, thesignal is applied for a specific amount of time per day. In certain suchembodiments, the signal is applied for 10 min, 20 min, 30 min, 40 min,50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23h per day. In certain such embodiments, the signal is appliedcontinuously for the specified amount of time. In certain alternativesuch embodiments, the signal may be applied discontinuously across theday, provided the total time of application amounts to the specifiedtime.

In certain embodiments wherein the controller causes the signal to beapplied intermittently, the signal is applied only when the subject isin a specific physiological state. For example, in certain embodiments,the signal may be applied only when the subject is asleep, and/or onlywhen the subject is undergoing an apnoeic episode.

In certain such embodiments, the apparatus further comprises acommunication, or input, element via which the status of the subject(e.g. that they are going to sleep) can be indicated by the subject or aphysician. In alternative embodiments, the apparatus further comprises adetector configured to detect the status of the subject, wherein thesignal is applied only when the detector detects that the subject is inthe specific state.

In certain embodiments, the one or more detected physiologicalparameters are selected from: sympathetic tone; diaphragmatic tone;genioglossus tone; blood pressure; respiratory rate; tidal volume; upperairway resistance, central respiratory drive.

In certain embodiments, the one or more detected physiologicalparameters comprise an action potential or pattern of action potentialsin a nerve of the subject, wherein the action potential or pattern ofaction potentials is associated with sleep apnoea. In certain suchembodiments, the nerve is part of the cervical sympathetic chain. Incertain such embodiments, the nerve is a superior cervical ganglion.

It will be appreciated that any two or more of the indicatedphysiological parameters may be detected in parallel or consecutively.For example, in certain embodiments, the controller is coupled to adetector or detectors configured to detect the pattern of actionpotentials in a superior cervical ganglion and also to detect the bloodpressure of the subject.

In certain embodiments, the detector detects that the subject or patientis undergoing an apnoeic episode characterised by one or morephysiological parameters being at or beyond the threshold value for eachparameter. In response, the controller causes a signal to be appliedeither bilaterally, unilaterally (right) or unilaterally (left),depending on which parameters characterise the apnoeic episode. Forexample, if the apnoeic episode is characterised predominantly by adetected increase in blood pressure, the controller might cause thesignal to be applied unilaterally to the left CSC,SCG and/orpostganglionic branch thereof. By way of further example, if the apnoeicepisode is characterised predominantly by a detected increase inrespiratory rate and/or decrease in tidal volume, the controller mightcause the signal to be applied unilaterally to the right CSC, SCG and/orpostganglionic branch thereof. By way of yet further example, if theapnoeic episode is characterised predominantly by an increase in bloodpressure and a detected increase in respiratory rate and/or decrease intidal volume, the controller might cause the signal to be appliedbilaterally in order to treat all characterising parameters of theapnoeic episode.

In certain embodiments, the signal is permanently applied. That is, oncebegun, the signal is continuously applied to the nerve or nerves. Itwill be appreciated that in embodiments wherein the signal is a seriesof pulses, gaps between pulses do not mean the signal is notcontinuously applied.

In certain embodiments of the methods, the stimulation in neuralactivity caused by the application of the signal is temporary. That is,upon cessation of the signal, neural activity in the nerve or nervesreturns substantially towards baseline neural activity within 1-60seconds, or within 1-60 minutes, or within 1-24 hours, optionally 1-12hours, optionally 1-6 hours, optionally 1-4 hours, optionally 1-2 hours.In certain such embodiments, the neural activity returns substantiallyfully to baseline neural activity. That is, the neural activityfollowing cessation of the signal is substantially the same as theneural activity prior to the signal being applied—i.e. prior tomodulation.

In certain alternative embodiments, the stimulation in neural activitycaused by the application of the signal is substantially persistent.That is, upon cessation of the signal, neural activity in the nerve ornerves remains substantially the same as when the signal was beingapplied—i.e. the neural activity during and following stimulation issubstantially the same.

In certain embodiments, the stimulation in neural activity caused by theapplication of the signal is partially corrective, preferablysubstantially corrective. That is, upon cessation of the signal, neuralactivity in the nerve or nerves more closely resembles the pattern ofaction potentials observed in a healthy subject than prior tomodulation, preferably substantially fully resembles the pattern ofaction potentials observed in a healthy subject. In such embodiments,upon cessation of the signal, the pattern of action potentials in thenerve or nerves resembles the pattern of action potentials observed in ahealthy subject. It is hypothesised that such a corrective effect is theresult of a positive feedback loop.

In certain such embodiments, once first applied, the signal may beapplied intermittently or permanently, as described in the embodimentsabove.

As is known by the skilled person, mammals have a left and a rightCSC-SCG complex. Therefore, in certain embodiments, the signal isapplied bilaterally. That is, in such embodiments, the signal is appliedto a CSC, SCG and/or postganglionic branch thereof on both the left andright side of the subject such that the neural activity is stimulated inthe nerves to which the signal is applied—i.e. the modulation isbilateral. In such embodiments, the signal applied to each nerve, andtherefore the extent of stimulation is independently selected from thatapplied to the other nerve or nerves. In certain embodiments the signalapplied to the right nerve or nerves is the same as the signal appliedto the left nerve or nerves. In certain alternative embodiments thesignal applied to the right nerve or nerves is different to the signalapplied to the left nerve or nerves.

In certain embodiments wherein the modulation is bilateral, each signalis applied by a neuromodulation device comprising one or moretransducers for applying the signal. In certain such embodiments, allsignals are applied by the same neuromodulation device, that device haveat least two transducers, one to apply the signal to the left nerve(s)and one to apply the signal to the right nerve(s). In certainalternative embodiments, each signal is applied by a separateneuromodulation device.

In certain embodiments of the methods according to the invention, thesignal applied is an electrical signal, an electromagnetic signal(optionally an optical signal), a mechanical (optionally ultrasonic)signal, a thermal signal, a magnetic signal or any other type of signal.

In certain such embodiments in which more than one signal may beapplied, for example when the modulation is bilateral, each signal maybe independently selected from an electrical signal, an optical signal,an ultrasonic signal, and a thermal signal. In those such embodiments inwhich two signals are applied by one modulation device, the two signalsmay be the same type of signal or may be different types of signalindependently selected from an electrical signal, an optical signal, anultrasonic signal, and a thermal signal. In those embodiments in whichtwo signals are applied, each by a separate neuromodulation device, thetwo signals may be the same type of signal or may be different types ofsignal independently selected from an electrical signal, an opticalsignal, an ultrasonic signal, and a thermal signal.

In certain embodiments in which the signal is applied by aneuromodulation device comprising at least one transducer, thetransducer may be comprised of one or more electrodes, one or morephoton sources, one or more ultrasound transducers, one more sources ofheat, or one or more other types of transducer arranged to put thesignal into effect.

In certain embodiments, the signal is an electrical signal, for examplea voltage or current. In certain such embodiments the signal comprises adirect current (DC) waveform, such as a charge balanced DC waveform, oran alternating current (AC) waveform, or both a DC and an AC waveform.

In certain embodiments, the signal applied is an electrical signal, forexample a voltage or current. In certain such embodiments the signalapplied comprises a direct current (DC) waveform, such as a chargebalanced direct current waveform, or an alternating current (AC)waveform, or both a DC and an AC waveform.

In certain embodiments, the DC waveform or AC waveform may be a square,sinusoidal, triangular or complex waveform. The DC waveform mayalternatively be a constant amplitude waveform.

It will be appreciated by the skilled person that the current/voltageamplitude of an applied electrical signal necessary to achieve theintended stimulation will depend upon the positioning of the electrodeand the associated electrophysiological characteristics (e.g.impedance). It is within the ability of the skilled person to determinethe appropriate current amplitude for achieving the intended stimulationin a given subject. For example, the skilled person is aware of methodssuitable to monitor the neural activity profile induced by neuronal ornerve stimulation.

In certain embodiments, wherein the signal comprises an AC waveformand/or a DC waveform, each waveform has an independently selectedfrequency of 0.5-100 Hz, optionally 1-50 Hz, optionally of 1-25 Hz,optionally 1-10 Hz. In certain embodiments, the signal has a frequencyof 1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, 3 Hz, 3.5 Hz, 4 Hz, 4.5 Hz, 5 Hz, 5.5 Hz,6 Hz, 6.5 Hz, 7 Hz, 7.5 Hz, 8 Hz, 8.5 Hz, 9 Hz, 9.5 Hz, 10 Hz, 15 Hz, 20Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, 50 Hz. In certain embodiments,the signal is an electrical signal having a frequency of 5 Hz, 7.5 Hz,10 Hz, or 20 Hz. It will be appreciated by those of skill in the artthat the lower and upper limits of such ranges can vary independently,such that the signal can have a frequency of at least 1 Hz, or at least2.5 Hz, or at least 5 Hz, or at least 10 Hz, or at least 20 Hz, or atleast 25 Hz, or at least 50 Hz, or at least 100 Hz. Such a signal canhave a frequency less than 1 kHz, or 500 Hz, or 200 Hz, or 100 Hz, or 50Hz or 20 Hz, or 10 Hz.

In certain embodiments, the signal is an electrical signal having avoltage of 1-20V. In certain preferred embodiments, the signal has avoltage of 5-15V, optionally 10-15V. In certain preferred embodimentsthe voltage is selected from 5V, 10V and 15V.

In certain embodiments, the signal is an electrical signal having acurrent of 0.1-5 mA, optionally 0.5-2 mA, optionally 0.75-1.5 mA,optionally 0.8-1 mA. In certain embodiments, the signal is an electricalsignal having a current of at least 0.1 mA, at least 0.2 mA, at least0.3 mA, at least 0.4 mA, at least 0.5 mA, at least 0.6 mA, at least 0.7mA, at least 0.8 mA, at least 0.9 mA, at least 1.0 mA. It will beappreciated by those of skill in the art that the lower and upper limitsof such ranges can vary independently, such that the signal can have acurrent of at least 0.1 mA, or at least 0.2 mA, or at least 0.3 mA, orat least 0.4 mA, or at least 0.5 mA, or at least 0.8 mA. Such a signalcan have a current less than 5 mA, or 2 mA, or 1.5 mA, or 1 mA, or 0.8mA. In certain preferred embodiments the signal has a current of lessthan 0.8 mA.

In certain embodiments the signal is an electrical signal having a pulsewidth of 0.1-5 ms, optionally 0.5-5 ms, optionally 1-3 ms, optionally 2ms. In certain embodiments, the signal is an electrical signal having apulse width of 0.2-5 ms. In certain embodiments, the signal has a pulsewidth of 0.1 ms, or 0.2 ms, or 0.5 ms, or 1 ms. It will be appreciatedby those of skill in the art that the lower and upper limits of suchranges can vary independently, such that the signal can have a pulseduration of at least 0.05 ms, 0.1 ms, 0.2 ms, 0.5 ms, 1 ms or 2 ms. Sucha signal can have a pulse duration less than 5 ms, 3 ms, 2 ms, 1 ms, 0.5ms, 0.2 ms, or 0.1 ms.

In certain preferred embodiments, the signal comprises an AC waveform of7.5 Hz 0.8 mA, or an AC waveform of 7.5 Hz 1 mA, or an AC waveform of7.5 Hz 10V. In certain preferred embodiments, the signal comprises an ACwaveform, has a current of at least 0.8 mA, has a pulse duration of 2ms, and has a frequency selected from 2.5 Hz, 5 Hz, 7.5 Hz, 10 Hz, 20 Hzor 50 Hz. In certain preferred embodiments, the signal comprises an ACwaveform, has a current of at least 0.5 mA, has a frequency of 5 Hz, andhas a pulse duration selected from 0.1 ms, 0.2 ms, 0.5 ms, 1 ms or 2 ms.

In those embodiments in which the signal applied is an electricalsignal, each transducer configured to apply the electrical signal is anelectrode, for example a cuff or wire electrode. In certain suchembodiments, all the transducers are electrodes configured to apply anelectrical signal, optionally the same electrical signal.

In a fourth aspect, the invention provides a neuromodulatory electricalwaveform for use in treating sleep apnoea in a subject, wherein thewaveform is an alternating current (AC) or direct current (DC) waveformhaving a frequency of 1-50 Hz, such that, when applied to a CSC, SCGand/or postganglionic branch the waveform stimulates neural signallingin the nerve. In certain embodiments, the waveform, when applied to thenerve, relieves or prevents sleep apnoea.

In a fifth aspect, the invention provides use of a neuromodulationdevice for treating sleep apnoea in a subject by stimulating neuralactivity in a CSC, SCG and/or postganglionic branch thereof of thesubject. In certain embodiments, the device is an apparatus or system asdescribed herein. In certain embodiments, the device delivers a signalto a CSC, SCG and/or postganglionic branch thereof of the subject.

In a preferred embodiment of all aspects of the invention, the subjector patient is a mammal, more preferably a human.

In a preferred embodiment of all aspects of the invention, the signal orsignals is/are applied substantially exclusively to the nerves or nervefibres specified, and not to other nerves or nerve fibres.

The foregoing detailed description has been provided by way ofexplanation and illustration, and is not intended to limit the scope ofthe appended claims. Many variations in the presently preferredembodiments illustrated herein will be apparent to one of ordinary skillin the art, and remain within the scope of the appended claims and theirequivalents.

EXAMPLES

The present inventors have developed a therapeutic method and apparatusfor stimulating the cervical sympathetic chain (CSC), e.g., unilaterallyor bilaterally, including, for example, the superior cervical ganglion(SCG) to treat sleep apnoea. This is illustrated by the followingexamples.

Example 1 Results

Bilateral CSC/SCG Stimulation Reduces Apnoeas and Disordered Breathingin Conscious Rats

Hypoxic-hypercapnic (H-H) gas challenge is a recognised model forinducing and analysing disordered breathing, including apnoeas.Conscious Sprague-Dawley rats were exposed to H-H gas challenge andbilateral stimulation of CSC (or sham) was applied.

As seen in FIG. 4, bilateral stimulation of the CSC markedly reduces theoccurrence of disordered breathing, including apneas, in rats that uponreturn to room-air following a hypoxic-hypercapnic (H-H) gas challenge(Indicated as “Post” in FIG. 4A).

FIG. 4B shows that the frequency of apnoeas is greatly reduced as aresult of bilateral CSC stimulation, as is the duration of each apnoeicepisode. This results in a greatly reduced aggregate time spent in anapnoeic state.

Bilateral CSC/SCG Stimulation Improves Cardioventilatory Performance andDecreases Upper Airway Resistance

In an alternative animal model (anaesthetised spontaneously hypertensiverats (SHR)), bilateral CSC stimulation resulted in a decrease in meanarterial blood pressure (FIG. 5A). Bilateral stimulation also resultedin an increase in diaphragmatic tone (an increase in diaphragm EMGactivity) and an increase in genioglossus tone (an increase ingenioglossus EMG activity) (FIGS. 5B and C). These effects weredose-dependent according to frequency of the stimulation, with 10 Hzproviding the greatest effect of the frequencies tested. Such changes indiaphragmatic and genioglossus tone are indicative of improvedrespiratory rate and a retracted tongue, respectively. Bilateralstimulation also resulted in a decrease in upper airway resistance (FIG.5D), a further measure of improved breathing patterns.

To further validate these findings, bilateral CSC stimulation wasperformed in an additional animal model. Hypoxic challenge ofanaesthetised Zucker-fat rats is a recognised model of obstructive sleepapnoea.

As shown in FIG. 6A, upper airway pressure rose markedly in anesthetizedZucker-fat rats during a 60 second exposure to a hypoxic gas challenge(8% O₂, 92% N₂) (UAP—no Stimulation). This rise in upper airway pressurewas markedly diminished in Zucker-fat rats in which the left and rightCSCs were being stimulated (5 Hz, 0.8 mA, 2 ms) during the hypoxicchallenge.

Similarly, FIG. 6B shows that mean arterial blood pressure (MAP, BP—noStimulation) fell markedly in anesthetized Zucker-fat rats during a60-second exposure to a hypoxic challenge (8% O₂, 92% N₂). This drop inblood pressure was markedly diminished in Zucker-fat rats in which bothCSCs were being stimulated (7.5 Hz, 0.8 mA, 2 ms) during the hypoxicchallenge.

Further evidence of improved ventilatory performance as a result of CSCstimulation is shown in FIG. 7. In particular, control anesthetizedZucker-fat rats display a substantial number of sighs (periods ofincreased respiratory effort) as defined by changes in genioglossusmuscle EMG (GG-EMG; FIG. 7, top left panel). As seen in FIG. 7 (topright panel), GG-EMG was increased (positive impact on the tongue) andthe incidence of sighs was markedly diminished for up to 3 hours afterbilateral CSC stimulation (1 min, 7.5 Hz, 0.8 mA, 2 ms).

Bilateral and Unilateral CSC Stimulation Promotes Retraction of theTongue and Increases Opening of the Airway

Unilateral and bilateral CSC stimulation (0.8 mA 7.5 Hz, 2 ms) markedlyaugmented genioglossus-EMG (GG-EMG) activity during hypoxic-hypercapnicgas challenge (10% O2, 5% CO2, 85% N2) in Zucker-fat rats (FIG. 8).Increased GG-EMG activity promotes contraction of the tongue, furthervalidating that CSC stimulation enhances opening of the airway.

Unilateral Left, Unilateral Right, and Bilateral Stimulation can be Usedto Elicit a Differential Response

A surprising finding was that by stimulating the left CSC only, theright CSC only, or both, the induced response could be tailored toresult in improvements in different parameters. As shown in FIG. 9A,mean arterial blood pressure (MAP, bottom trace) fell dramatically inZucker-fat rats upon stimulation of the left CSC (FIG. 9A, left panel,bottom trace). MAP fell minimally with right CSC stimulation (FIG. 9A,middle panel, bottom trace), and combined left and right CSC stimulationcaused a transient fall in MAP that was followed by a sustained increase(FIG. 9A, right panel, bottom trace).

In contrast, right CSC stimulation had a greater effect on breathing(diaphragmatic-EMG; top trace) than left CSC stimulation (FIG. 9A, toptrace, left and centre panel). It is noted that this fall in respiratoryrate was in response to a highly beneficial increase in tidal volume(data not shown). FIG. 9B summarizes these findings from Zucker-fat ratsand supports the conclusions that differential stimulation of the leftand right CSCs, or both, can elicit different responses.

The ability of unilateral left, unilateral right, and bilateralstimulation of the CSC to elicit different responses was also observedin relation to muscle activity. As seen in FIG. 10 (top left panel), theexposure of a Zucker-fat rat to a H-H gas challenge (10% O₂, 5% CO₂, 85%N₂) causes a small amount of genioglossus-EMG activity, consistent withretraction of the tongue (FIG. 10, top trace, left panel). H-H gaschallenge also results in an increase in diaphragmatic-EMG indicative ofan increase in breathing frequency (left panel, middle trace) as well asa biphasic change in blood pressure (left panel, bottom trace). As seenin the other panels of FIG. 10, concurrent stimulation of the left, moreso the right, and especially bilateral electrical stimulation of theCSCs markedly enhances the genioglossus-EMG responses (indicative ofincreased retraction of the tongue) and diminishes the changes in bloodpressure during H-H challenge.

The finding that CSC stimulation promotes opening of the upper airway byretraction of the tongue was entirely unexpected, as the CSC was notpredicted to control skeletal muscle such as the genioglossus. Theobserved effects further strengthen the evidence that unilateral (leftor right) and bilateral electrical stimulation of the CSC is aneffective therapy for sleep apnoea since both central and obstructivesleep apnoea in humans heavily involves the malposition of the tongueover the airway which blocks airflow.

CSC Stimulation is Effective at a Number of Signal Amplitudes

As shown in FIG. 11, the observed improvements in blood pressure (MeanArterial Pressure (MAP)) and respiratory rate as a result of CSCstimulation could be induced across a range of current amplitudes. Asignal having a current amplitude of 0.5 mA elicited a small effect; asignal having a current amplitude of 1.0 mA elicited a greater effect;the most efficacious signal was one having a current amplitude of 0.8mA.

Hypoglossal Stimulation is Less Effective than CSC Stimulation

Attempts to treat sleep apnoea in the prior art have includedstimulation of the hypoglossal nerve. However, FIG. 12 shows that unlikeCSC stimulation, stimulation of the hypoglossal nerve does not affectthe increases in diaphragmatic-EMG (top trace) and falls in arterialblood pressure (bottom trace) in Zucker-fat rats that occur duringhypoxic-hypercapnic gas challenge (10% O₂, 5% CO₂, 85% N₂) (FIG. 12,left panel control rats; right panel hypoglossal stimulation). CSCstimulation thus provides a more effective treatment for sleep apnoea.

Example 2

Anaesthetised Zucker fat rats (15-18 wks) underwent bilateralstimulation of the CSC (using cuff electrodes). The signal applies was 5Hz, 2 ms pulse width, with current of 0.1 mA, 0.5 mA, 0.8 mA or 1.2 mA.The results are shown in FIG. 13. 0.8 mA current resulted in a decreasein airway pressure and an increase in blood pressure. Current of 1.2 mAresulted in a marked decrease in airway pressure as well as decrease inblood pressure.

Changes in stimulation frequency also differentially impacted bloodpressure and upper airway pressure. High frequency stimulations decreaseblood pressure sharply versus lower frequencies—for example, 2.5 Hzresulted in only a small drop in blood pressure versus more significantfalls when higher frequencies were used (FIG. 14). Bilateral stimulationusing 0.5 mA, 2 ms pulse width, 5 Hz was determined to result in upperairway pressure being decreased significantly without blood pressuredropping significantly (FIG. 14).

Changes in stimulation pulse width also differentially impacted bloodpressure and upper airway pressure. High pulse width stimulationsdecrease blood pressure sharply versus lower pulse widths. (FIG. 15)Bilateral stimulation using 0.5 mA, 5.0 Hz, 0.2 ms pulse width wasdetermined as resulting in upper airway pressure decreasingsignificantly without blood pressure dropping significantly (FIG. 15).

Chronic Stimulation

Methods: All surgical procedures were performed in a sterile surgicalsuite with Male Zucker Fat Rats (15-20 wks) were administered 4-5%isoflurane via vaporizer and nosecone. Once anesthetized isoflurane wasreduced to 1-2%. The anesthetic plane was monitored via toe pinch andrespiration while surgical procedures are conducted. An incision wasmade between the eyes to between the ears to reveal the skull. 3 screwswere drilled in the skull to help secure the stimulating headcap. Theheadcap was reinforced with dental cement. The wired cuff electrodeswere trochared next to the cervical sympathetic chain. Once the CSC wasisolated and placed into the cuff, Tisseel, a fibrinogen, was placedaround the electrode/nerve interface to secure the electrode. Aftersurgery rats were immediately placed in their home cages in a warmingcabinet set at 30° C. for up to an hour. After that rats were housedindividually on soft bedding and given pellets on the floor for 7 days.Surgical wounds were observed daily and animals weighed. Dry cereal madeinto a paste and rehydration fluid was made available per vet consult.All external skin sutures were removed after 2 weeks. The animal wasused for conscious studies 2 weeks after surgery or until a return tobaseline weight.

Results

Double plethysmography chambers were used to assess changes in airwayresistance in animals after stimulation. Bilateral CSC stimulation (0.5mA, 5 Hz, 0.2 ms, 5 min recovery between stimuli) showed decreases in(FIG. 16A): upper airway resistance (Sraw); time delay between thoracicand nasal flow signals (dT); time of inspiration (TI); end expiratorypause (EEP); and end inspiratory pause (EIP) (FIG. 16). Response (%Change) was calculated by comparing each rat to baseline values for thesame rat prior to first stimulation. S1-S3 represent 3 separatestimulations 5 minutes apart.

The same bilateral stimulation also resulted in an increase in (FIG.16B): respiratory frequency (Freq); tidal volume (TV); minuteventilation (MV); central respiratory drive defined by (TV/TI); peakinspiratory flow (PIF); peak expiratory flow (PEF); and bronchodilation(EF 50). Response (% Change) was calculated by comparing each rat tobaseline values for the same rat prior to stimulation. S1-S3 represent 3separate stimulations 5 minutes apart.

Continuous bilateral stimulation (0.5 mA, 5.0 Hz, 0.2 ms) for 3 minutesevery 10 minutes decreased airway resistance during stimulation.Following stimulation for 3 minutes, airway resistance was increasedrelative to baseline (FIG. 17).

Intermittent stimulation (bilateral, 0.5 mA, 5.0 Hz, 0.2 ms) in whichthe signal was applied 30 s on and 30 s off resulted in a markeddecrease in airway resistance both during stimulation and progressivelyafter each stimulation (FIG. 18). Intermittent stimulation was appliedfor 15 minutes every hour, for 6 hours.

Whole body plethysmography was used to assess the effect of intermittentstimulation on the number of disordered breaths. Bilateral acuteintermittent CSC stimulation (0.5 mA, 5 Hz, 0.2 ms) was applied toconscious freely moving Zucker Fat (14 wk) male. As shown in FIG. 19(left-hand bars), stimulation resulted in increases in: Tidal Volume(TV); Minute Ventilation (MV); Central Respiratory Drive defined by(TV/TI).

The observed reduction in disordered breaths (apnoeas) followingintermittent stimulation was continued when the stimulation protocol wasapplied for 7 consecutive days (FIG. 19, right-hand bars, and FIG. 20).Bilateral acute intermittent CSC stimulation (0.5 mA, 5 Hz, 0.2 ms) inconscious freely moving Zucker Fat (14 wk) male were stimulated for 7consecutive days following the acute intermittent stimulation protocolof 30 s on/off for 15 minutes every hour and were able to reduce thenumber of disordered breaths (defined by breath that were two times aslong as the average Te/Ti) during the week of stimulation (FIG. 20)(n=3). It was reduced by 39% on the first day and 53% on the 7th day.The number of disordered breaths returned after the stimulation protocolended.

1.-69. (canceled)
 70. An apparatus for treating sleep apnoea in asubject, the apparatus comprising: i. at least one implantable neuralinterfacing element having one or more electrodes configured to deliveran electrical signal to at least one cervical sympathetic chain (“CSC”),superior cervical ganglion (SCG) and/or postganglionic branch thereof ofthe subject and positioned in signalling contact with a left cervicalsympathetic chain (“CSC”), superior cervical ganglion (SCG) and/orpostganglionic branch thereof or a right cervical sympathetic chain(“CSC”), superior cervical ganglion (SCG) and/or postganglionic branchthereof; and ii. a controller operably coupled to the neural interfacingelement, which controller programs the neural interfacing element todeliver the electrical signal that increases localized sympatheticactivity of the CSC, SCG and/or postganglionic branch, wherein increasedsympathetic activity of the CSC, SCG and/or postganglionic branchameliorates sleep apnoea in the subject.
 71. An apparatus for modulatingthe neural activity of a CSC, SCG and/or postganglionic branch of asubject, the apparatus comprising: a neural interfacing elementcomprising one or more transducers each configured to apply anelectrical signal to a CSC, SCG and/or postganglionic branch thereof ofthe subject and placed in signalling contact with a left cervicalsympathetic chain (“CSC”), superior cervical ganglion (SCG) and/orpostganglionic branch thereof each or a right cervical sympathetic chain(“CSC”), superior cervical ganglion (SCG) and/or postganglionic branchthereof; and a controller operably coupled to the one or moretransducers, the controller controlling the signal to be applied by eachof the one or more transducers, such that the signal stimulatesincreased localized sympathetic activity in the CSC, SCG and/orpostganglionic branch in the subject.
 72. The apparatus of claim 70,wherein the one or more electrodes is one or more cuff electrodes. 73.The apparatus of claim 71, wherein the one or more transducers is one ormore cuff electrodes.
 74. The apparatus according to claim 70,comprising at least two electrodes coupled to the controller andconfigured to apply an electrical signal to a CSC, SCG and/orpostganglionic branch thereof of the subject.
 75. The apparatusaccording to claim 74, wherein the at least two electrodes arepositioned bilaterally to increase localized sympathetic activity of theright and left CSC, SCG and/or postganglionic branch thereof.
 76. Theapparatus according to claim 70, wherein the signal is initiated at afirst frequency and then altered to a second frequency, wherein (a) thefirst frequency is higher than the second frequency; or (b) the firstfrequency is lower than the second frequency.
 77. The apparatusaccording claim 70, wherein the controller is configured to cause thesignal to be delivered intermittently.
 78. The apparatus according toclaim 77, wherein the controller causes the signal to be delivered for afirst time period, then stopped for a second time period, then reappliedfor a third time period, then stopped for a fourth time period, whereinthe duration of each of the first, second, third and fourth time periodsis independently selected from: 0.8 s-2 min, 0.8 s-30 s, 0.8 s-10 s, 0.8s-5 s, 0.8-2 s, 10 s-2 min, 30 s-2 min, 30 s-1 min, optionally 30 s. 79.The apparatus according to claim 70, wherein the increase in localizedsympathetic activity in the CSC, SCG and/or postganglionic branchthereof produces one or more of: a decrease in duration of apnoeicepisodes, a decrease in frequency of apnoeic episodes, a decrease inblood pressure, a decrease in respiratory rate, an increase in tidalvolume, a decrease in upper airway resistance, an increase indiaphragmatic muscle activity, an increase in genioglossus muscleactivity, an increase in central respiratory drive, and the actionpotential or pattern of action potentials in the CSC, SCG and/orpostganglionic branch more closely resembling that exhibited by ahealthy individual than before the application of the signal.
 80. Theapparatus according to claim 70, wherein the increase in localizedsympathetic activity in the CSC, SCG and/or postganglionic branchthereof results in at least one of an increase in tidal volume, adecrease in upper airway resistance, an increase in diaphragmatic muscleactivity and an increase in genioglossus muscle activity.
 81. Theapparatus according to claim 70, wherein the apparatus further comprisesa detector element to detect one or more physiological parameters in thesubject, wherein one or more of the detected physiological parameters isselected from sympathetic tone; diaphragmatic tone; genioglossus tone;blood pressure; respiratory rate; tidal volume; upper airway resistance;central respiratory drive.
 82. The apparatus according to claim 81,wherein the controller is coupled to said detector element, and causessaid one or more transducers each to apply said signal when thephysiological parameter meets a predefined value.
 83. The apparatusaccording to claim 70, wherein the stimulation in neural activity as aresult of the one or more transducers applying the signal issubstantially persistent.
 84. The apparatus according to claim 70,wherein the stimulation in neural activity is temporary.
 85. Theapparatus according to claim 70, wherein the apparatus is suitable forfull implantation into the subject.
 86. A method for increasingsympathetic activity in a CSC, SCG and/or a postganglionic branchthereof of a subject: implanting in the subject at least a portion of anapparatus for modulating the neural activity of a CSC, SCG and/orpostganglionic branch of a subject, the apparatus comprising: a neuralinterfacing element comprising one or more transducers each configuredto apply an electrical signal to a CSC, SCG and/or postganglionic branchthereof of the subject and placed in signalling contact with a leftcervical sympathetic chain (“CSC”), superior cervical ganglion (SCG)and/or postganglionic branch thereof each or a right cervicalsympathetic chain (“CSC”), superior cervical ganglion (SCG) and/orpostganglionic branch thereof; and i. a controller operably coupled tothe one or more transducers, the controller controlling the signal to beapplied by each of the one or more transducers, such that the signalstimulates increased localized sympathetic activity in the CSC, SCGand/or postganglionic branch in the subject; ii. positioning at leastone transducer of the apparatus in signalling contact with the CSC, SCGand/or postganglionic branch thereof of the subject; and iii. activatingthe apparatus.
 87. The method according to claim 86, wherein increasingsympathetic activity in the CSC, SCG and/or postganglionic branchthereof ameliorates a condition of sleep apnoea in the subject.
 88. Themethod according to claim 86, wherein an increase in sympatheticactivity in the CSC, SCG and/or a postganglionic branch thereof isindicated by one or more of a decrease in blood pressure, a decrease inrespiratory rate, an increase in tidal volume, a decrease in upperairway resistance, an increase in diaphragmatic muscle activity, anincrease in genioglossus muscle activity, an increase in centralrespiratory drive.